An inflammatory response is known as a protective response of living organism for rehabilitating the structures and functions of tissues damaged by infection, trauma, etc. Mobilization of leukocytes to a focus of inflammation is critical for the rapid resolution of infections and restoration of tissue damages resulting from a variety of injuries. However, a misdirected or prolonged inflammatory response causes damage to the body's tissues or diseases. For example, inflammatory diseases are caused by bacterial or viral infection, e.g., cerebrospinal meningitis, enteritis, dermatitis, uveitis, encephalitis, or adult respiratory distress syndrome, or non-infectious factors, e.g., trauma, autoimmune diseases, or organ transplantation rejection. Inflammatory diseases are classified into acute and chronic inflammatory diseases according to symptoms or pathological features. Acute inflammation such as allergy or bacterial/viral infection is manifested as local signs such as a change in bloodstream, blood vessel size, and vascular permeability, and the recruitment of leukocytes. In contrast, a main pathological feature of chronic inflammation such as rheumatoid arthritis, artherosclerosis, chronic kidney infection, or hepatocirrhosis is a continuous emigration of macrophages, lymphocytes, or plasma cells into foci of inflammation due to recurrence of inflammatory factors, thereby causing a long-lasting inflammatory response.
In order to induce an inflammatory response, the emigration of leukocytes into inflammation foci is an essential event. Many cell adhesion molecules are implicated in the emigration of leukocytes. That is, the emigration of leukocytes includes a rolling stage in which leukocytes are mobilized to the blood vessels of inflamed sites by chemokine secreted from the inflamed sites and then rolled on surfaces of vascular endothelial cells while reducing the velocity of cell movement; an adhesion stage in which the leukocytes stops rolling and are firmly adhered to the vascular endothelial cells; and a transmigration stage wherein the leukocytes migrate through capillary vessels and basement membranes. The final stage, i.e., the transmigration stage is also called “diapedesis” or “transendothelial migration”.
Cancer cells induced by carcinogens proliferate rapidly relative to normal cells, thereby forming tumor masses, invading surrounding tissues, and interfering with normal body functions. Cancer cells bring nutrients and oxygen by inducing angiogenesis, and metastasis thereof is also caused by angiogenesis. Although cancer cells grow infinitely at specific sites, they can also leave the sites from which they originated, migrate to and grow in new sites, whose process is called “metastasis”. Metastasis involve several key steps: conversion of cancer cells to migratory mesenchymal cells, dissociation of the mesenchymal cells from the original tumor sites, invasion into and spread through surrounding connective tissues and capillary vessels, migration through blood vessels, escape from the blood vessels, migration through connective tissues, and proliferation in secondary sites.
Expression and activation of cell adhesion molecules on surfaces of tumor cells play a very important role in tumor metastasis (Zetter, B. R. (1993). Adhesion molecules in tumor metastasis. Semin Cancer Biol. 4: 219). Tumor metastasis is induced by regulating the expression pattern and activity of cell adhesion molecules on surfaces of tumor cells. In order to understand the metastasis of tumor cells, it is prerequisite to understand cell adhesion molecules and substances for regulating the expression and functions of the cell adhesion molecules (Bailly, M., Yan, L., Whitesides, G. M., Condeelis, J. S., and Segall, J. E. (1998). regulation of Protusion Shape and Adhesion to the sustratum during chemoacic esponses of mammalian carcinoma cells. Exp Cell Res. 241: 285; Frisch, S. M., Vuori, K., Ruoslahti, E., and Chan-Hui., P. (1996). Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 134: 793; and Hannigan, G. E., Leung-Hagesteijn, C., Fitz-Gibbon, L., Coppolino, M. G., Radeva, G., Filmus, J., Bell, J. C., and Dedhar, S. (1996). Regulation of cell adhesion and anchorage-dependent growth by a new β1-integrin-linked protein kinase. Nature 379: 91).
Meanwhile, the present inventors have disclosed that CD99 (MIC2) molecule, which is one of the transmembrane proteins, regulates an intercellular adhesion by regulating a cell surface expression of LFA-1 (Hahn, J. H., Kim, M. K., Choi, E. Y., Kim, S. H., Sohn, H. W., Ham, D. I., Chung, D. H., Kim, T. J., Lee, W. J., Park, C. K., Ree, H. J., and Park, S. H. (1997) CD99 (MIC2) regulates the LFA-1/ICAM-1-mediated adhesion of lymphocytes, and its gene encodes both positive and negative regulators of cellular adhesion. J. Immunol. 159: 2250). CD99 is a type I transmembrane protein composed of a glycosylated extracellular domain, a transmembrane domain, and a short intracellular domain (Banting, G. S., Pym, B., Darling, S. M., and Goodfellow P. N. (1989). The MIC2 gene product: epitope mapping and structural prediction analysis define an integral membrane protein. Mol. Immunol. 26: 181). Although there has not been much research about the function of the CD99 molecule, it has been presumed that the CD99 molecule is associated with cell adhesion, on the basis of the observations that the engagement of the CD99 molecule with anti-CD99 monoclonal antibody induces homotypic cell aggregation of various lymphoid cell lines as well as double-positive thymocytes (Bernard, A., Aubrit, F., Raynal, B., Pham, D., and Boumsell, L. (1988). A T cell surface molecule different from CD2 is involved in spontaneous rosette formation with erythrocytes. J Immunol 140: 1802; and Bernard, G., Zoccola, D., Deckert, M., Breittmayer, J., Aussel, C., and Bernard. A. (1995). The E2 molecule (CD99) specifically triggers homotypic aggregation of CD4+ CD8+ thymocytes. J. Immunol. 154: 26).
The present inventors have found that CD99 is involved in the migration of monocytes through connective tissues (Kim Y K., 2004. Regulation of MMP-9 gene expression by CD99 type II in the monocytes. Kangwon National University). The present inventors have also disclosed that when CD99 is activated, the function of β1 integrin is altered, thereby preventing the adhesion of cancer cells onto extracellular matrices (ECMs). This suggests that CD99 may be involved in metastasis of cancer cells (Suh J S., 2001. Control of invasiveness of human breast carcinoma cell line MCF-7 by CD99 molecule. Kangwon National University). In addition, Muller W A et al. have disclosed that inflammatory diseases can be cured by inhibiting the CD99-mediated transmigration of leukocytes (Schenkel A R, Mamdouh Z, Chen X, Lieman R M, Muller W A (2002) CD99 plays a major role in the migration of monocytes through endothelial junctions. Nat Immunol 3:143; and US. Patent Publication No. 2003/0211099).